Decades of research has shown that long-term changes in synaptic function ultimately require changes in gene expression.Recent work has focused on nuclear signaling by calcium and protein messengers initiated at postsynaptic sites. In this issue of The EMBO Journal, Ivanova and colleagues show that shuttling of CtBP-1 between presynaptic areas and nuclei regulates gene expression, which reminds us that presynaptic zones should not be ignored when considering synapse-to nucleus signaling.